Medical oral microbiology II – lecture (ZLLM0421p)

1. Medical oral microbiology II – lecture (ZLLM0421p) Antiifectives II (antibiotics other than cell wall acting, antivirotics, antimycotics, antiparasital agents) Ondřej Zahradníček zahradnicek@fnusa.cz

2. N N Polypeptidic antibiotics N N N • Acting on cytoplasmic membrane • Highly toxic: ototoxic (= hearing), nephrotoxic (= kidney) • Polymyxin B is used only localy(e. g. part of ear drops Otosporin) • Polymyxin E – colistin is exceptionally used also for systemic treatment • Acting on not dividing bacteria, too • Rezistant bacteria are: all Gram-positive bacteria, all bacteria of genus Proteus, Providencia, Morganella and Serratia

3. Quinolone antibiotics (synthetic) I „ • Acting on nucleic acids(inhibition of gyrase) • Bactericidal except 1st generation • Do not use under 15 years (growth cartilage) • I. generation (non-fluorated quinolones as oxolinic acid) is used rarely now • II.A generation (norfloxacin – e. g. Nolicin, Lexinor, Noroxin, Quinabic, Janacin) for urinary tract infections only • II.B generation – for systemic use: ofloxacin (Floxin, Oxaldin, Tarivid), ciprofloxacin (Ciplox, Ciphin, Ciprinol, Ciprobay, Cipro), pefloxacin (Abaktal, Peflacine)

4. Quinolone antibiotics (synthetic) II • III. generation: grepafloxacin, sparfloxacin, levofloxacin (Tavanic) – more effect to resistant streptococci, but in Europe not needed (other drugs are sufficiently effective), so this generation is almost used in the U. S. • IV. generation: moxifloxacin (Avelox), similar to previous, besides gyrase also inhibits topoisomerase IV • Global characteristic of quinolones: their spectre is quite large, but secondary resistances often develop quickly  practical use is limited and they are recently not recommended as „drugs of 1st choice“

5. Quinolone antibiotics – examples Names of individual drugs are very variable

6. Nitroimidazoles • They act on nucleic acid synthesis of anaerobic bacteria only; on the other hand, they also have effect to some protozoa (Trichomonas vaginalis, Entamoeba histolytica) • They have no effect for aerobic bacteria, so they should be never used for treatment of other than anaerobic or protozoan diseases. On the other hand, they have often effect against Clostridium difficile strains (but not all strains) • Used drugs are metronidazole (Klion, Entizol, Efloran) and ornidazole (Avrazor, Tiberal)

7. Examples of nitroimidazoles

8. Aminoglycosidyes • Effect is bactericidalin the initial phase of proteosynthesis • They are ototoxic and nephrotoxic • Synergy with beta-lactams– lower toxicity • Streptomycin is recently only used as antituberculotic. Recently used drugs are gentamicin,netilmicin, amikacin • Neomycin with bacitracin (a drug of another group) =combined drug for topic use (Framykoin, Pamykon), also in triple combination with polymyxin B (Neosporin) • Effect to Gram-negative bacteria and staphylococci, but not strepto/enterococci

9. Examples of aminoglycosides

10. Macrolides, lincosamids, streptogramins, tetracyclins, amphenicols • All these antibiotics act on proteosynthesis, but not its initial phase. All these drugs have bakteriostatic effect • Macrolids, lincosamids and streptogramins are with exceptions (Haemophilus, some anaerobic G– bacteria) only effective against Gram-positive bacteria. These three groups also use to have common resistances (for all of them) • Tetracyclins and amphenicols have broad spectre

11. Tetracycline antibiotics • Quite broad spectre, but risk of secondary resistances • They should be never used for children younger than 8 years – teeth development • Used less than before, but useful for some atypical pneumonias, some gynaecologic infections etc.) • Rather than classic tetracycline, today‘s commonly used drug is doxycycline (Deoxymykoin). It is also used for malaria prophylaxis. • New glycylcycline antibiotics are related; tigecycline (Tygacil) is a broad spectre drug, but also this one has its limitations

12. Macrolides (incl. ketolides, azalides) • I. generation: erythromycin, classic macrolide, and II. generation:roxithromycin (Rulid), josamycin (Wilprafen): rare use today • III. generation: clarithromycin (Klacid), azithromycin (Azithrox, Sumamed). Azithromycine is sometimes considered to be a special group (azalide) Macrolides are good drugs against mycoplasmas and chlamydias. They also can be used as alternative drugs against streptococci or staphylococci, but they should not be considered drugs of first choice here. In some situations it is also recommended to use them against gonorrhoea

13. Lincosamids + streptogramins • Used lindosamids are lincomycine (Lincocin) a clindamycine (Dalacin C) • They have good access to bone marrow  use in orthopaedy, surgery including stomatosurgery • Also used for topic treatment of acne • Very good effect against anaerobic bacteria with important exception of Clostridium difficile – risk of intestinal infection after use (pseudomembranous enterocolitis) • Streptogramins are less commonly used drugs against strepto- and enterococci (Quinupristin + dalfopristin as Synercid)

14. Amphenicoles • The only one used in human medicine is chloramphenicole • Broad spectre and nearly no cross-resistances with other antibiotics are advantages • Very good access to CSFis another advantage • Big problem: important haematotoxicity (= alteration of blood cells production) • Used as topic treatment (eye drops), for systemic treatment only as a reserve for failure of other treatment possibilities

15. Macrolides and lincosamides – examples

16. Tetracyclines and amphenicols – examples

17. Macrocyclic and oxazolidinone antibiotics • Both these groups are new antibiotics available against some resistant Gram-positive bacteria. They have both effect against proteosynthesis • Oxazolidinone antibiotics are used against resistant enterococci and staphylococci, typical representative is linezolid (Zyvox, Zyvoxid). It is bacteriostatic • Macrocyclic antibiotics are used against resistant strains of Clostridium difficile, representative is fidaxomicin (Dificlir)

18. Folate synthesis inhibitors • Since 1960 a commonly used combination of two drugs is used; they inhibit successive steps of folate synthesis and so they have synergic effect. • I is a sulphonamide sulfametoxazole combined with a pyrimidin antibiotic trimetoprim – combination is usually called co-trimoxazole – (Septrin, Biseptol, Bactrim, Cotrim, Sumetrolim, Septra…) • In this combination, the effect is bactericidal. It can be used against UTI, but also some respiratory infections. It has even surprisingly good access to cerebrospinal fluid and has some effect against malaria (in some countries it is used for malaria prophylaxis)

19. Nitrofurantoin • Effect on saccharide metabolism. Its effect is bacteriostatic. It has relatively broad spectre • It is used for urinary bladder inflammations, as it only has sufficient concentrations in urine, not in other tissues • Related nifuratel is used as topical treatment in gynaecology (as Macmiror, or with an antimycotic as Macmirorcomplex) • The patients should know that the urine becomes strongly yellow during use of this drug. This yellow colour is also visible on the agar at in vitro testing (diffusion disc test)

20. Examples of co-trimoxazole

21. Antituberculotics • Antituberculotics are special drugs used against tuberculosis. Only some of them are also used against „normal bacteria“ • Unlike antibiotics they are always used in combinations of three of usually four drugs (intra- and extracellular effect, effect against resistant strains) • The most common antituberculotics are: • Ethambutol (EMB or E) • Isoniazid (INH or H) • Pyrazinamide (PZA or Z) • Rifampicin (RMP or R) • Streptomycin (SM or S)

22. Antivirotics (virostatics) • They are only used against serious viral infections, common infections are mostly treated symptomatically • In many viral diseases there is no sufficiently effective treatment • In practice, laboratory susceptibility testing is not yet used (only experimentally) • Treatment only reflects the experience with changes of effectivity of individual drugs • They often have effect only in incubation period or first phase of infection (typically in herpes)

23. Survey of antivirotics (except antiretrovirotics)

24. Drugs with effect against herpesviruses (virus of herpes, shingles, but also mononucleosis) • Used for topic and systemic treatment • Effect against viral replication • Doses every 8 to 12 hours • Aciclovir is suitable for herpes simplex; for shingles, it is possible to use it, but the injection form is required • For cytomegaloviral infections we use ganciclovir, valaganciclovir, cidofovir and foskarnet. They have better effect, but also worse toxicity than aciclovir

25. Herpes simplex treatmentfamciclovir, valaciclovir, aciclovir opt.pacificu.edu/ce/catalog/14382-AS/Herpes.html

26. Shingles www.aafp.org/afp/20000415/2437.html. hebra.dermis.net/content/e404/e456/index_ger.html

27. Drugs against influenza • Used in persons with depressed immunity • Unlike vaccination it is not possible to use it for primary prevention of healthy persons, some of them can be used for prophylaxis (= in persons maybe already infected, but not ill) • Older: amantadin + rimantadin, loss of effect (against classic types of virus). They inhibit penetration of the virus and its incorporation into the cell • Oseltamivir (Tamiflu) andzanamivir (Relenza) are more modern and more effective drugs, their effect includes new strains of the virus. They act as inhibitors of neuraminidase

28. Antiretrovirotics (againts HIV) • Until now, no definitive treatment exists, but it is possible to prolong life of the infected persons (they might die because on something else) and to inhibit the transmission to foetus • Problem is that these drugs are often not available for the most affected areas (Africa). It is possible to supply these countries by cheaper variants, but there is the risk of illegal reexport to Europe and the U. S. • Besides HIV infection treatment, it is also necessary to solve opportune infections etc.

29. Survey of antiretrovirotics

30. Antimycotics • Antimycotics are drugs with antifungal activity. • Topic antimycotics are used for non-complicated skin and mucosal infections • Systemic treatment is needed for more serious mycoses, but sometimes also for mucosal (vaginal mycosis – to eradicate the fungi from the intestinal reservoir) • It is necessary to treat real mycoses, not accidental findings of fungi • It is also important to know, WHY the mycosis started (immunodeficiency? Broad-spectre antibiotics? Diabetes? Hormones?) and never forget to treat the basic disease

31. Polyene antimycotics: amphotericin B • Polyene antimycotics are related with macrolidic antibiotics • Amphotericin B is an effective, but highly nephrotoxic antimycotic • It influences permeability of the cytoplasmic membrane • It has poor effect against dermatophytes (skin filamentous fungi), but it has good effect against yeasts even at resistance against other antimycotics. • Less toxic form: amphotericin B in intralipid (Ambisome)

32. Other polyene antimycotics • Nystatin has effect almost against candida and is used to eliminate intestinal reservoir of candida infection • Natamycin is similar, has also anti-trichomonas effect (good in vaginal tablets) • These drugs, too, have no effect against dermatophytes

33. Imidazole antimycotics • Topic and systemic drugs, unlike majority of others also for oral use • Mechanism of effect:Inhibition of synthesis of ergosterol in the membrane • Minimal unwanted side effects • Useful for skin and mucosal, but not systemic mycoses • Examples: mikonazole,ketokonazole, and only local clotrimazole, econazole, bifonazole, oxikonazole and fentikonazole

34. Triazole antimykotics • They are more effective than imidazoles, not so much by spectre of effect, rather by farmacologic properties • They can be used for systemic mycoses treatment • Examples: itraconazole, fluconazole and newer voriconazole • Fluconazoleis well effective, but Candida crusei is primarily resistant • Itraconazole is drug of choice for bronchopulmonary aspergillosis. It is used orally

35. Nucleotide analogons • Flucytosin (5-fluorocytosin) is changed into a cytostatic in the cell of a fungus, but humans cells no not metabolize it • It is not recommended for monotherapy we rather combine it with amphotericin B. • In children, monotherapy can be used for urinary tract candidosis

36. Echinocandins • Caspofungin (Cancidas) is an echinocandinantimycotic for treatment of invasive candidosis and aspergillosis • It inhibits fungal cell wall(b-glucane) • It is the only one that is fungicidal in Candida. It filamentous fungi it is fungistatic • Resistances are not common • Newer anidulafungin (Ecalta) is similar Allylamins • Terbinafin and naftifin are newer drugs agains dermatomycoses

37. Survey of antimycotic use

38. Antiparasital drugs • „Antiparasital drugs“ is global term for drugs with antiparasital activity • In fact, this group is very variable, as also parasites are variable • In vitro susceptibility is not tested • Chemoprofylaxis of malaria – only case of use of an antimicrobial drug for long term prophylaxis and not only treatment • Antiprotozoics, anthelmintics and drugs against ectoparasites are in this group

39. Mechanism of effect of antiparasitics • Antiprotozoics mostly interfere with enzyme systems of infectious agents • Anthelmintics are vermifugal (the helminth escapes) or vermicidal (the helminth is killed) • Anthelmintics may paralyze muscles (piperazine), block respiration (pyrvinium), influence neuromuscular apparatus (levamisole) influence matabolism of glucose (mebendazole) or cause muscle contractions (prasiquantel) • Antiectoparazitics (against arthropods) may have different mechanisms

40. Diseases caused by protozoa 1 • In pathogenic intestinal protozoa we use almost metronidazole, in cryptosporidia it is spiramycin • In Naegleria fowleriwe use amphotericin B • For ocular acantamoebiasis there is topic dibrompropamid • Intrichomonosisit is metronidazolornatamycin • In pneumocystosis we use co-trimoxazole, pentamidin and others

41. Diseases caused by protozoa 2 • Treatment of malaria should be consulted with experts, important is not just species of plasmodium, but also its geographic origin • Chloroquinandprimaquinare for some cases • Sometimes, especially for tropical malaria, we come backto quinine • Treatment of toxoplasmosis contains pyrimetamin, sulphonamides etc. • Leishmaniosis is treated by antimony

42. Nematode infections • For threadwormswe use pyrvinium or pyrantel • For common roundworms, but also many other helminths (Trichuris, Ancylostoma, Necator) we use mebendazole • Suitable drug against filariosis is diethylkarbamazin • For Trichinella spiralis(from wild hog meat), dog roundworm(larva migrans) and some other we use thiabendazole • For Dracunculus medinensisit is possible to use metronidazole

43. Diseases caused by flukes and tape-worms • For flukesof all species (Schistosoma, Fasciola etc.) we use praziquantel • Against tape-worms of genus Taenia, Diphylobothrium and Hymenolepis we can use niklosamide or praziquantel • For Ecchinococcusalbendazol + surgical extraction of the helminth Schistosoma haematobium http://www.infovek.sk/predmety/biologia/metodicke/ploskavce/index.php

44. Ectoparasital diseases • In lice it is good to consult treatment with an expert – actually best available drug is not always well effective • The same can be said for Sarcoptes scabiei and other parasites • We use for instance hexachlorcyclohexane, lindan, permethrin and their combinations • In blood-sucking insects we have to combine chemical protection (repellents) with mechanical protection (sufficiently dense network in tropical countries)

45. Good bye! http://umanitoba.ca/outreach/evidencenetwork/wp-content/uploads/2015/07/ROTENBERG_Antibiotics-%E2%80%93-overprescribed-and-under-effective.jpg